Journal article
Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios
PLoS genetics, Vol.17(7), p.e1009584
07/09/2021
DOI: 10.1371/journal.pgen.1009584
PMCID: PMC8270211
PMID: 34242216
Abstract
Author summary Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). While nearly forty risk genes have been identified for CL/P, few risk genes are known for CP. We used a new statistical method, PLACO, to identify genetic variants influencing risk of both CL/P and CP either in the same direction or in opposite directions. In a combined multi-ethnic genome-wide study of 2,771 CL/P and 611 CP case-parent trios, we discovered 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Of these loci, 2 were identified at the genome-wide threshold, and the rest at a suggestive significance threshold of 10(-6). Locus-specific effects appear to vary by racial/ethnic group at these regions of genetic overlap. We replicated the shared genetic etiology of subtypes underlying CL/P, and further discovered loci of genetic overlap exhibiting etiologic differences. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.
Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts- the most common craniofacial birth defects in humans- are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 x 10(-8), PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10(-6), we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.
Details
- Title: Subtitle
- Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios
- Creators
- Debashree Ray - Johns Hopkins UniversitySowmya Venkataraghavan - Johns Hopkins UniversityWanying Zhang - Johns Hopkins UniversityElizabeth J. Leslie - Emory UniversityJacqueline B. Hetmanski - Johns Hopkins UniversitySeth M. Weinberg - University of PittsburghJeffrey C. Murray - University of IowaMary L. Marazita - University of PittsburghIngo Ruczinski - Johns Hopkins UniversityMargaret A. Taub - Johns Hopkins UniversityTerri H. Beaty - Johns Hopkins University
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.17(7), p.e1009584
- DOI
- 10.1371/journal.pgen.1009584
- PMID
- 34242216
- PMCID
- PMC8270211
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7404
- eISSN
- 1553-7404
- Publisher
- Public Library Science
- Number of pages
- 28
- Grant note
- R03DE029254 / National Institute of Dental and Craniofacial Research; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR) R03DE029254; R03DE027121; R00DE025060; R01DE016148; U24OD023382 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 07/09/2021
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985035883802771
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